Anti-tumor therapies comprising a combination of a cartilage extract and an anti-neoplastic agent providing high efficacy and low toxic side effects.
This invention relates to anti-tumor therapies which comprises anti-neoplastic agents and a cartilage extract having anti-tumor activity.
Present assignee already described the biological activities recovered from cartilage tissue, namely from shark cartilage. The processes of obtention of cartilage extracts and the properties of the extracts themselves are disclosed in international publications WO 95/32722, WO 96/23512 and WO 97/16197. The processes generally comprise the steps of: homogenizing and extracting shark cartilage until a mixture of cartilage particles of an average size of about 500 xcexcm and a crude liquid extract are obtained, separating said particles from said crude liquid extract, and fractionating said crude liquid extract so as to recover molecules having a molecular weight lower than about 500 KDa. These processes apply to the extraction of biological activities from any source of cartilage.
Shark cartilage liquid extracts have been tested in various assays and they comprise anti-angiogenic, anti-collagenolytic, direct anti-tumor proliferating and anti-inflammatory activities.
These cartilage extracts are described as being efficient against tumors and nevertheless innocuous since no serious adverse effect directly related to their oral administration has been observed in treated animals and human patients. The shark cartilage liquid extract and any other cartilage extract having equivalent anti-tumor activities are all within the scope of this invention and will be referred to as xe2x80x9ccartilage extracts.xe2x80x9d
A large panel of therapeutic agents is known for treating cancer. Anti-neoplastics include, but are not limited to, those of the following TABLE 1:
Most of these anti-neoplastics or anti-tumor agents have a low safety margin since they are highly toxic, e.g. they provide severe undesirable effects at effective dosages.
It is an accepted fact, in the medical field, that no anti-tumor therapy is perfect. Pharmacologists and oncologists always have to deal with a compromise between a maximally effective dose and the toxic side effects thereof. As a result, an effective dose of a neoplastic may be given in a sub-maximal dose to avoid too severe toxic side effects to any possible extent. So, avoidance of severe toxic side effects unfortunately often has the priority of concern over maximal efficacy.
The cartilage extracts that we already described (op. cit.) are active in vivo against tumor proliferation, which activity appears to be due to a combination of at least a direct anti-tumor activity, anti-collagenolytic and anti-angiogenic activities. This extract has a well-proven anti-tumor activity and is devoid of toxic side effects. Since the current studies in the field aim at obtaining an anti-tumor therapy which would have close to 100% efficacy with close to 0% toxicity, it will be readily appreciated that anti-tumor compositions approaching these gold standards would be greatly welcome.
There is therefore a need for anti-neoplastic therapies combining high anti-tumor efficacy and low toxic side effects.
There is now provided improved anti-tumor therapies comprising administering an effective anti-tumor amount of an anti-neoplastic agent and an effective anti-tumor amount of a cartilage extract.
The overall advantageous contribution of the cartilage extract is addition to the efficacy of the anti-neoplastic and protection against toxic side effects.
It is therefore an object of the present invention to provide a use of a cartilage extract having anti-tumor activity in a combined anti-tumor therapy, to increase anti-tumor activity of an anti-neoplastic in a patient who is administered an anti-tumor amount of that anti-neoplastic and to protect the patient against an increase of toxic side effects inherent to the administration of the anti-neoplastic.
Combined anti-tumor therapy may take two forms: 1) administering to the patient a composition of an anti-neoplastic and a cartilage extract, and 2) administering to the patient an anti-neoplastic and a cartilage extract, separately, in a time-overlapping or simultaneous fashion (generally defined as xe2x80x9cconcurrent treatmentxe2x80x9d).
In a specific embodiment, the cartilage extract is a shark cartilage extract obtained by a process comprising the steps of: homogenizing and extracting shark cartilage until a mixture of cartilage particles of an average size of about 500 xcexcm and a crude liquid extract are obtained, separating said particles from said crude liquid extract, and fractionating said crude liquid extract so as to recover molecules having a molecular weight lower than about 500 KDa.
In a first preferred embodiment, the anti-tumor amount of the anti-neoplastic is a sub-optimal dose thereof, and the amount of cartilage extract given in combination adds anti-tumor efficacy to the anti-neoplastic with no increase, even better a decrease, of toxic side effects inherent to the administration of higher dose of the anti-neoplastic which would have an anti-tumor efficacy equivalent to the combined anti-tumor therapy.
In a second preferred embodiment, the anti-tumor amount of the anti-neoplastic is an optimal dose thereof, and the amount of cartilage extract given in combination adds anti-tumor efficacy to the anti-neoplastic with no increase, even better a decrease, of toxic side effects inherent to an administration of said anti-neoplastic.
The choice of a sub-optimal or optimal dose of an anti-neoplastic merely depends on the aggressivity sought for a treatment and the severity of the side effects of the anti-neoplastic.
The anti-neoplastic may be busulfan, thiotepa, chlorambucil, cyclophosphamide, estramustine sodium phosphate, ifosfamide, mechlorethamine hydrochloride, melphalan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, methotrexate sodium, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, hydroxyurea, daunorubicin, doxorubicin hydrochloride, epirubicin hydrochloride, idarubicin hydrochloride, dactinomycin, bleomycin sulfate, mitomycin, mitotane, mitoxantrone hydrochloride, etoposide, teniposide, docetaxel, paclitaxel, vinblastine sulfate, vincristine sulfate, vindesine sulfate, vinorelbine tartrate, altretamine, amsacrine, I-asparaginase, dacarbazine, fludarabine phosphate, porfimer sodium, procarbazine hydrochloride, tretinoin (all-trans retinoic acid), marimastat, suramin, TNP 470, thalidomide or radiotherapy.
In a specific embodiment of the invention, the anti-neoplastic is cisplatin.
It is another object of this invention to provide products which may be used for bringing into practice the novel use for a cartilage extract.
One of the products is an anti-tumor composition comprising an anti-tumor amount of an anti-neoplastic and an anti-tumor amount of a cartilage extract, in a suitable pharmaceutically acceptable carrier.
Another one of these products is an anti-tumor treatment kit comprising a first component consisting of an anti-neoplastic in an anti-tumor dosage form and a second component consisting of a cartilage extract in an anti-tumor dosage form.
We have tested combined anti-tumor therapies comprising administering a cartilage extract and an anti-neoplastic, hoping to find out if the efficacy of each other may be improved without any increase, or better with a decrease, of toxic side effects.